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Tumour targeting of humanised cross-linked divalent-fab ' antibody fragments: a clinical phase I/II study

Casey, JL; Napier, MP; King, DJ; Pedley, RB; Chaplin, LC; Weir, N; Skelton, L; ... Begent, RHJ; + view all (2002) Tumour targeting of humanised cross-linked divalent-fab ' antibody fragments: a clinical phase I/II study. BRIT J CANCER , 86 (9) 1401 - 1410. 10.1038/sj/bjc/6600198.

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Abstract

Antibody engineering has made it possible to design antibodies with optimal characteristics for delivery of radionuclides for tumour imaging and therapy. A humanised divalent-Fab' cross-linked with a bis-maleimide linker referred to as humanised divalent-Fab' maleimide was produced as a result of this design process, It is a humanised divalent antibody with no PC, which can be produced in bacteria and has enhanced stability compared with F(ab')(2). Here we describe a clinical study in patients with colorectal cancer using humanised divalent-Fab' maleimide generated from the anti-carcinoembryonic antigen antibody A5B7 radiolabelled with iodine-131. Ten patients received an i.v. injection of iodine-131-labelled A5B7 humanised divalent-Fab' maleimide, and positive tumour images were obtained by gamma camera imaging in eight patients with known lesions, and one previously undetected lesion was identified. True negative results were obtained in two patients without tumour. Area under the curve analysis of serial blood gamma counting and gamma camera images showed a higher tumour to blood ratio compared to A5B7 mF(ab')(2) used previously in the clinic, implying this new molecule may be superior for radioimmunotherapy, MIRD dose calculations showed a relatively high radiation dose to the kidney, which may limit the amount of activity that could be administered in radioimmunotherapy, However the reduction in immunogenicity was also a major advantage for A5B7 humanised divalent-Fab' maleimide over murine versions of this antibody suggesting that humanised divalent-Fab' maleimide should be a useful vehicle for repeated therapies. (C) 2002 Cancer Research UK.

Type: Article
Title: Tumour targeting of humanised cross-linked divalent-fab ' antibody fragments: a clinical phase I/II study
DOI: 10.1038/sj/bjc/6600198
Keywords: humanised antibody, divalent-Fab ' maleimide, fragments, hDFM, imaging, colorectal cancer, phase I/II trial, CARCINOEMBRYONIC ANTIGEN, CIRCULATING ANTIGEN, MONOCLONAL-ANTIBODY, RADIOIMMUNOTHERAPY, PHARMACOKINETICS, BIODISTRIBUTION, TECHNOLOGY, THERAPY, TRIALS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/241184
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